Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

Abstract

Crohn's disease (CD) is one of main disease entities under the umbrella term chronic inflammatory bowel disease. The etiology of CD involves alterations in genetic, microbiological, and immunological factors. This review is devoted to the role of the bacterial wall compound muramyl dipeptide (MDP) for the activation of inflammatory pathways involved in the pathogenesis of CD. The importance of this molecule is underscored by the fact that (1) MDP, which is found in most Gram-negative and -positive bacteria, is able to trigger several immunological responses in the intestinal system, and (2) that alterations in several mediators of the MDP response including-but not restricted to-nucleotide oligomerization domain 2 (NOD2) are associated with CD. The normalization of MDP signaling is one of several important factors that influence the intestinal inflammatory response, a fact which emphasizes the pathogenic importance of MDP signaling for the pathogenesis of CD. The important aspects of NOD2 and non-NOD2 mediated effects of MDP for the development of CD are highlighted, as well as how alterations in these pathways might translate into the development of new therapeutic strategies.

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…7,[52][53][54][55][56][57][58] For instance, the SNPs in NOD2 are the most prominent risk-associated SNPs and can lead to early disease onset and a more complicated clinical course of Crohn disease, including fibrostenosis and fistulization. 11 These genetic variations also exhibit a marked reduction in bacterial autophagy due to the fact that NOD2 recruits ATG16L1 to the site of bacterial entry, 10 as described in more detail below. Genetic associations with Crohn disease have also been reported in the following other autophagy-related genes: IRGM (immunity-related GTPase family, M), 59 PTPN2 (protein tyrosine phosphatase, non-receptor type 2), 60 XBP1 (X-box binding protein 1), 61 LRRK2 (leucine-rich repeat kinase 2), 60,62 ULK1 63 and ATG16L1.…”

“…The most frequently described genetic variations are those in NOD2, which are strongly associated with early onset and ileal involvement, indicating a more complicated clinical course of the disease due to fibrostenosis and fistulization. 11,110 The contribution of the ATG16L1 variant T300A to the clinical phenotype is not well established, and more investigations are warranted.…”

“…8,9 Additionally, crosstalk between ATG16L1 and the cytosolic pathogen receptor NOD2 (nucleotide-binding oligomerization domain-containing 2), which initiates autophagy in response to invading pathogens, suggests the importance of these pathways in the pathogenesis of Crohn disease. 10,11 Consequently, there is growing interest in revealing the association between autophagy and this disorder.…”

Novel Regulatory Action of Ribosomal Inactivation on Epithelial Nod2-Linked Proinflammatory Signals in Two Convergent ATF3-Associated Pathways

“…Contact between the intestinal epithelium and microorganisms is facilitated through interactions between the pattern recognition receptors (PRRs) and bacterial Ags (1). In response to N-acetylmuramyl-Lalanyl-D-isoglutamine (MDP), a minimal peptidoglycan moiety of both Gram-positive and Gram-negative bacteria, nucleotidebinding oligomerization domain-containing protein 2 (Nod2) is activated and initiates a wide spectrum of innate recognition and immune responses (2,3). Acute Nod2 stimulation by MDP specifically activates proinflammatory NF-kB and MAPK cascades that mediate the expression of proinflammatory mediators, including cytokines (4,5).…”

Autophagy and checkpoints for intracellular pathogen defense

“…Pattern recognition receptors (PRRs) such as NOD-like receptors (NLRs), Toll-like receptors (TLRs), and RIG-I-like receptors (RLRs) are central players of innate immunity, capable of activating phagocytosis and various inflammatory processes, as well as chemokines and antimicrobial molecules. ATG16L1 is recruited by NOD1 and NOD2 to the bacterial entry site at the plasma membrane in epithelial cells, and silencing of NOD2 in monocyte-derived dendritic cells decreases LC3-II levels after treatment with the NOD2 ligand muramyldipeptide [51]. Recent data show that infected bone marrow-derived macrophages lacking caspase-1 show increased autophagy, attributed to caspase-1's ability to cleave the TLR adaptor TRIF [52].…”